Older age, lack of vaccination and infection with variants other than Omicron associated with severity of COVID-19 and in-hospital mortality in Pakistan (preprint)

Objectives: We investigated factors associated with COVID-19 disease severity and in-hospital mortality in a low-middle income setting. Methods: Records of 197 adult COVID-19 patients admitted to the Aga Khan University Hospital, Karachi between April 2021 and February 2022 were reviewed. Clinical data including, that of SARS-CoV-2 variants was collected. Results: The median age of the patients was 55 years and 51.8% were males. 48.2 % of patients had non-severe disease, while 52.8% had severe/critical disease. Hypertension (48%) and diabetes mellitus (41.3%) were most common comorbid conditions. Omicron (55.3%), Beta (14.7%), Alpha (13.7%), Delta (12.7%) and Gamma (3.6%) were identified in patients. The risk of severe disease was higher in those aged above 50 years (OR 5.73; 95%CI [2.45-13.7]) and in diabetics (OR 4.24; 95% CI[1.82-9.85]). Full vaccination (OR 0.25; 95%CI [0.11-0.58]) or infection with Omicron variants (OR 0.42; 95% CI[0.23-0.74]) reduced disease severity. Age > 50 (OR 5.07; 95%CI [1.92-13.42]) and presence of myocardial infarction (OR 5.11; 95% CI[1.45-17.93]) was associated with increased mortality, but infection with Omicron (OR 0.22 95% CI 0.10-0.53]) reduced risk. Conclusions: Vaccination was found to protect against severe COVID-19 regardless of the infecting variant and is recommended especially, in those aged over 50 years and with co-morbid conditions.

The Emergence of COVID-19 Associated Mucormycosis: Analysis of Cases From 18 Countries (preprint)

Coronavirus disease 2019 (COVID-19)–associated mucormycosis (CAM) has recently been increasingly reported, particularly among patients with uncontrolled diabetes. Patients with diabetes and hyperglycemia often display an inflammatory state that may be potentiated by the activation of antiviral immunity to SARS-CoV-2, and thus may favor secondary infections. We analyze 80 published and unpublished cases of CAM, with a predominance (42/80) of cases from India. Uncontrolled diabetes mellitus as well as systemic corticosteroid treatment represented major comorbid predisposing factors and rhino-orbital cerebral mucormycosis was the most frequent presentation of disease. Mortality was high at 49%, driven particularly by those with pulmonary or disseminated mucormycosis and those with cerebral involvement. Furthermore, a significant proportion of surviving patients suffered life-changing morbidities (loss of vision in 46% of survivors). Our review indicates that CAM may be a relevant complication of severe COVID-19, particularly in those with uncontrolled diabetes. Funding: Martin Hoenigl received funding from Astellas for two investigator initiated studies (ISR005824 and ISR005838), and was supported by the National Institutes of Health, Grant UL1TR001442. Agostinho Carvalho was supported by the Fundação para a Ciência e a Tecnologia (FCT) (UIDB/50026/2020 and UIDP/50026/2020), the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) (NORTE-01-0145-FEDER-000039), the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 847507, and the “la Caixa” Foundation (ID 100010434) and FCT under the agreement LCF/PR/HR17/52190003.Declaration of Interest: MH received research funding from Gilead, Pfizer, Astellas, Scynexis and NIH. JPG received speaker and expert advice fees from Pfizer and Gilead. NK has received research grants or honoraria as a speaker or advisor from Astellas, Gilead, MSD, and Pfizer, outside the submitted work. KL received consultancy fees from SMB Laboratoires Brussels, MSD and Gilead, travel support from Pfizer, speaker fees from FUJIFILM WAKO, Pfizer and Gilead, a service fee from Thermo fisher Scientific. OAC is supported by the German Federal Ministry of Research and Education, is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy – CECAD, EXC 2030 – 390661388 and has received research grants from, is an advisor to, or received lecture honoraria from Actelion, Allecra Therapeutics, Al-Jazeera Pharmaceuticals, Amplyx, Astellas, Basilea, Biosys, Cidara, Da Volterra, Entasis, F2G, Gilead, Grupo Biotoscana, Immunic, IQVIA, Janssen, Matinas, Medicines Company, MedPace, Melinta Therapeutics, Menarini, Merck/MSD, Mylan, Nabriva, Noxxon, Octapharma, Paratek, Pfizer, PSI, Roche Diagnostics, Scynexis, and Shionogi. PLW performed diagnostic evaluations and received meeting sponsorship from Bruker, Dynamiker, and Launch Diagnostics; Speakers fees, expert advice fees and meeting sponsorship from Gilead; and speaker and expert advice fees 489 from F2G and speaker fees MSD and Pfizer. Is a founding member of the European Aspergillus PCR Initiative. ACh received funding support from educational grant of Pfizer, MSD Pharmaceutical Ltd, and Gilead. All other authors no conflicts.Ethical Approval: MISSING

Risk Factors for Bacterial Infections in Patients With Moderate to Severe COVID-19: a Case Control Study (preprint)

ObjectiveBacterial infections are known to complicate respiratory viral infections and are associated with adverse outcomes in COVID-19 patients. A case control study was conducted to determine risk factors for bacterial infections where cases were defined as moderate to severe/critical COVID-19 patients with bacterial infection and those without were included as controls. Logistic regression analysis was performed.  ResultsOut of a total of 50 cases and 50 controls, greater proportion of cases had severe or critical disease at presentation as compared to control i.e 80% vs 30% (p<0.001). Hospital acquired pneumonia (72%) and Gram negative organisms (82%) were predominant. Overall antibiotic utilization was 82% and was 64% in patients who had no evidence of bacterial infection. The median length of stay was significantly longer among cases compared to controls (12.5 versus 7.5 days) (p=0.001). The overall mortality was 30%, with comparatively higher proportion of deaths among cases (42% versus 18%) (p=0.009). Severe or critical COVID-19 at presentation (AOR: 4.42 times; 95% CI; 1.63-11.9) and use of steroids (AOR: 4.60; 95% CI 1.24-17.05) were independently associated with risk of bacterial infections. These findings have implications for antibiotic stewardship as antibiotics can be reserved for those at higher risk for bacterial superinfections. 

Risk factors for bacterial infections in patients with moderate to severe COVID-19: A case control study (preprint)

ObjectiveBacterial infections are known to complicate respiratory viral infections and are associated with adverse outcomes in COVID-19 patients. A case control study was conducted to determine risk factors for bacterial infections where cases were defined as moderate to severe/critical COVID-19 patients with bacterial infection and those without were included as controls. Logistic regression analysis was performed. ResultsOut of a total of 50 cases and 50 controls, greater proportion of cases had severe or critical disease at presentation as compared to control i.e 80% vs 30% (p<0.001). Hospital acquired pneumonia (72%) and Gram negative organisms (82%) were predominant. Overall antibiotic utilization was 82% and was 64% in patients who had no evidence of bacterial infection. The median length of stay was significantly longer among cases compared to controls (12.5 versus 7.5 days) (p=0.001). The overall mortality was 30%, with comparatively higher proportion of deaths among cases (42% versus 18%) (p=0.009). Severe or critical COVID-19 at presentation (AOR: 4.42 times; 95% CI; 1.63-11.9) and use of steroids (AOR: 4.60; 95% CI 1.24-17.05) were independently associated with risk of bacterial infections. These findings have implications for antibiotic stewardship as antibiotics can be reserved for those at higher risk for bacterial superinfections.

Long term impact on lung function of patients with moderate and severe COVID-19. A prospective cohort study (preprint)

IntroductionA significant number of patients continue to recover from COVID-19; however, little is known about the lung function capacity among survivors. We aim to determine the long-term impact on lung function capacity in patients who have survived moderate or severe COVID-19 disease in a resource-poor setting. Methods and analysisThis prospective cohort study will include patients aged 15 years and above and have reverse transcriptase-polymerase chain reaction (RT-PCR) positive for COVID 19 (nasopharyngeal or oropharyngeal). Patients with a pre-existing diagnosis of obstructive or interstitial lung disease, lung fibrosis and cancers, connective tissue disorders, autoimmune conditions affecting the lungs, underlying heart disease, history of syncope and refuse to participate will be excluded. Pulmonary function will be assessed using spirometry and diffusion lung capacity for carbon monoxide (DLCO) at three- and six-months interval. A chest X-ray at three and six-month follow-up and CT-chest will be performed if clinically indicated after consultation with the study pulmonologist or Infectious Disease (ID) physician. Echocardiogram (ECHO) to look for pulmonary hypertension at the three months visit and repeated at six months if any abnormality is identified initially. Data analysis will be performed using standard statistical software. Ethics and disseminationThe proposal was reviewed and approved by ethics review committee (ERC) of the institution (ERC reference number 2020-4735-11311). Informed consent will be obtained from each study participant. The results will be disseminated among study participants, institutional, provincial and national level through seminars and presentations. Moreover, the scientific findings will be published in high-impact peer-reviewed medical journals. Strengths and Limitations of this study- The study has the potential to develop context-specific evidence on the long-term impact on lung function among COVID-19 survivors - Findings will play key role in understanding the impact of the disease on vital functions and help devise rehabilitative strategies to best overcome the effects of disease - This is a single-center, study recruiting only a limited number of COVID-19 survivors - The study participants may loss-to-follow up due to uncertain conditions and disease reemergence

Gender Differences in COVID-19; A Narrative Review (preprint)

As the COVID-19 pandemic continues to affect millions of people worldwide, its predilection for the male gender has continued to baffle scientists and there is a need for understanding factors which underlie this association. An overwhelming body of evidence from both developed and developing countries has shown that not only is there male preponderance for infection with SARS-Cov-2 but there is a greater severity of illness as well as mortality difference between sexes. These differences could be attributed to enhanced T-cell mediated immune responses in females and low androgen levels; the evidence for which has been extrapolated by studies evaluating differential responses to viral infections between sexes. There is also an increased risk of thromboembolic complications of COVID-19 infection in males which is a major cause of morbidity and mortality. Moreover behavioural differences between genders has also been postulated to play a role in acquisition and predisposition to SARS-Cov-2 infection.

Treatment of ARDS and hyperinflammation in COVID-19 with IL-6 antagonist Tocilizumab: a tertiary care experience from Pakistan (preprint)

Cytokine release syndrome in COVID-19 is characterized by hyperinflammation which manifests as ARDS, multi-organ failure, and high inflammatory parameters. Tocilizumab, an IL-6 antagonist has been used in COVID-19 acute respiratory distress syndrome (ARDS) with conflicting results from different parts of the world. We conducted a retrospective descriptive study from Feb 2020 to May 2020 on COVID-19 patients with ARDS and hyperinflammation characterized by raised CRP and/or ferritin. A total of 244 patients with COVID-19 were admitted out of which 107 had ARDS. Thirty patients had both ARDS and hyperinflammation and received tocilizumab. The mean age was 62.5 years (SD: 13.5) and the majority were male (83%). The mean CRP pre-treatment was 217.5 mg/L and post 48 to 72 hours of tocilizumab treatment was 98.5 mg/L. Twenty-one patients (70%) also received concomitant intravenous methylprednisolone. Of the 30 patients, 7 died and 20 recovered. Ten patients required intensive care unit admission and nine developed nosocomial infections. COVID-19 associated aspergillosis was diagnosed in three patients post tocilizumab treatment. Mortality was significantly higher in patients who developed a nosocomial infection and who required intermittent positive pressure ventilation (IPPV). Our study is the first to describe the treatment outcomes with tocilizumab from a low-middle income country. The availability and cost of tocilizumab in our region which makes it imperative to understand its potential for use in our setting. Our study supports the use of tocilizumab in a select patient population with COVID-19 and recommends monitoring of nosocomial infections and opportunistic infections.

Transcriptomic profiling of disease severity in patients with COVID-19 reveals role of blood clotting and vasculature related genes (preprint)

COVID-19 caused by SARS-CoV-2 manifests as a range of symptoms. Understanding the molecular mechanisms responsible for immuno-pathogenesis of disease is important for treatment and management of COVID-19. We examined host transcriptomes in moderate and severe COVID-19 cases with a view to identifying pathways that affect its progression. RNA extracted from whole blood of COVID-19 cases was analysed by microarray analysis. Moderate and severe cases were compared with healthy controls and differentially regulated genes (DEGs) categorized into cellular pathways. DEGs in COVID-19 cases were mostly related to host immune activation and cytokine signaling, pathogen uptake, host defenses, blood and vasculature genes, and SARS-CoV-2- and other virus- affected pathways. The DEGs in these pathways were increased in severe compared with moderate cases. In a severe COVID-19 patient with an unfavourable outcome we observed dysregulation of genes in platelet homeostasis and cardiac conduction and fibrin clotting with disease progression.